WO2016041530A1

WO2016041530A1 - Complexes of canagliflozin and cyclodextrins

Info

Publication number: WO2016041530A1
Application number: PCT/CZ2015/000106
Authority: WO
Inventors: Iva OBADALOVA; Ondrej Dammer; Jaroslava SVOBODOVA; Lukas KREJCIK; Ludek Ridvan; Marcela Tkadlecova
Original assignee: Zentiva, K.S.
Priority date: 2014-09-16
Filing date: 2015-09-15
Publication date: 2016-03-24
Also published as: CZ2014634A3

Abstract

The present invention relates to complexes of canagliflozin of formula I, (lS)-1,5-anhydro-1- (3-((5-(4-fluorophenyl)-2-thienyl)methyl)-4-methylphenyl)-D-glucitol; with cyclodextrins and a method of their preparation. These complexes can be advantageously used for stabilization of amorphous canagliflozin in terms of the chemical and polymorphic stability, β- Cyclodextrin, modified β-cyclodextrins and γ-cyclodextrin can be particularly used for the complexation of canagliflozin.

Description

Complexes of canagliflozin and cyclodextrins

Technical Field

The invention relates to complexes of canagliflozin of formula I

(X),

( 1 S)- 1 ,5-anhydro- 1 -(3 -((5-(4-fluorophenyl)-2-thienyl)methyl)-4-methylphenyl)-D-glucitol, with cyclodextrins and a method of their preparation. These complexes can be advantageously used for stabilization of amorphous canagliflozin in terms of the chemical and polymorphic stability. Preferably, β-cyclodextrin, modified β-cyclodextrins and γ-cyclodextrin can be used for the complexation of canagliflozin.

Canagliflozin is a highly selective inhibitor of the common transporter of sodium and glucose of type 2 (SGLT2), responsible for renal glucose reabsorption. Inhibition of SGLT-2 with canagliflozin increases excretion of glucose by the kidneys, which leads to a decrease of glycaemia and an improvement of diabetes compensation virtually without any increase of the risk of hypoglycaemia. This is a unique mechanism of action that is completely independent of the action of insulin. Currently, canagliflozin is approved in the U.S. and in Europe for treatment of type 2 diabetes mellitus in monotherapy (in case of intolerance to metformin), or in combination with other antidiabetic drugs, including insulin. Besides compensation of diabetes, administration of canagliflozin moderately reduces weight and the blood pressure. Thanks to its different action mechanism compared to other orally administered antidiabetic drugs or insulin, canagliflozin may be a convenient choice in a combination treatment of diabetes. Background Art

Canagliflozin and its preparation are described in the patent application WO05012326. The process described in this patent provides amorphous canagliflozin. The amorphous form of canagliflozin is characterized by chemical and polymorphic instability. Further, two forms of canagliflozin hemihydrate are known, which are described in the patent applications WO2008069327 and WO2009035969. Canagliflozin hemihydrate described in the patent application WO2009035969 corresponds to the form that is present in the dosage form Invokana^®. Also, cocrystals of canagliflozin are known, in particular with D- and L-proline, phenylalanine and citric acid, which are described in the patent applications WO2012154812 and WO 2013064909.

Disclosure of Invention

High instability is typical for amorphous canagliflozin; in a relatively short time it is subject to chemical degradation and an increase of impurities with a higher content than the defined limits allow. However, the amorphous form may be advantageously stabilized with cyclodextrins producing complexes that offer chemical and polymorphic stability and resistance to elevated temperatures, humidity and light. Under certain conditions a complex of canagliflozin with cyclodextrin is more stable than the crystalline form of canagliflozin hemihydrate. In particular, β-cyclodextrin, modified β-cyclodextrins, or γ-cyclodextrin can be used for the complexation. Last but not least, a complex of canagliflozin and a cyclodextrin can be used to purify the API itself. This invention provides preparation and characterization of these complexes of canagliflozin with cyclodextrins.

Detailed Description of Invention

Amorphous canagliflozin is characterized by high chemical and polymorphic instability. It changes its colour already at room temperature and usual humidity (50% RH) within a few days and the content of impurities increases. At the same time, due to atmospheric moisture, conversion of the amorphous form to the crystalline form of canagliflozin hemihydrate (according to patent application WO2009035969) occurs. Accordingly, the amorphous form of canagliflozin may be advantageously stabilized using a complex with cyklodextrin, which will prevent chemical degradation of canagliflozin and the increase of the contents of impurities and, moreover, it stabilizes the polymorphic form against undesired transformations.

In this case, β-cyclodextrin, modified β-cyclodextrins or γ-cyclodextrin was used as the cyclodextrin. Modified β-cyclodextrins refer to (2-hydroxyethyl)-P-cyclodextrin, (2- hydroxypropyl)-p-cyclodextrin, sodium salt of sulfobutyl ether- β-cyclodextrin, heptakis(2,3,6- tei-0-methyl)^-cyclodextrin and heptakis(2.6-di-0-memyl)^-cyclodextrin.

An association of canagliflozin and cyclodextrin by means of non-covalent bonds can be considered as a complex. The ability of cyclodextrins to form inclusion complexes, where organic or inorganic molecules (guest) can be included into the cavity of the cyclodextrin (host) is well-known. This phenomenon most frequently occurs in water or in a mixture of water and another polar solvent. The stoichiometry of such complexes depends on the size of the cavity and the character of the guest, while complexes of different stoichiometries may coexist in a solution in equilibrium.

The method of measurement of proton relaxation times Tl with the use of solid-phase NMR was used as evidence of complexation of canagliflozin and β-cyclodextrin. While the Tl value measured for amorphous canagliflozin alone was 3.5 s and Tl for β-cyclodextrin alone was 0.9 s, in the complex, all the protons (on canagliflozin as well as on β-cyclodextrin) exhibited the same relaxation time of 1.5 s. This phenomenon proves that canagliflozin and β- cyclodextrin are intermixed at the molecular level.

The preparation of a complex of canagliflozin and a cyclodextrin comprises the following steps:

a/ dissolving or dispersing the cyclodextrin in a solvent;

b/ adding canagliflozin;

c/ isolation of the complex

The cyclodextrin can be dissolved or dispersed in the solvent, preferably in water, at a temperature in the range from 20°C to the boiling point of the solvent. In the case of γ- cyclodextrin, the dissolution proceeds in water, best at a temperature of 20 to 40°C, while β- cyclodextrin dissolves in water best at 80 to 100°C.

Canagliflozin can be added in the amorphous form, as well as in the form of crystalline hemihydrate. The complex with cyclodextrin is produced equally readily in both the cases.

The complex of canagliflozin with cyclodextrin is generally produced in the yield of at least 90%, the chemical purity, measured with HPLC, not being lower than the chemical purity of the input canagliflozin. On the contrary, it often happens that the chemical purity of the complex is considerably higher than that of the input canagliflozin. Thus, a complex of canagliflozin with a cyclodextrin can be conveniently used for purification of crude canagliflozin.

Canagliflozm forms a complex with β-cyclodextrin, with modified β-cyclodextrins, or with γ- cyclodextrin in molar ratios of cyclodextrin to canagliflozin in the range of 0.5 : 1 to 2 : 1, but ideally 1 : 1.

The chemical and polymorphic stability of amorphous canagliflozin and of the complex of canagliflozin with β-cyclodextrin is compared in Table 1. When loading the amorphous canagliflozin with a higher temperature and humidity, degradation and a significant increase of impurities occur, the impurities of formula IMP-A and IMP-B having been identified as the main ones.

(IMP-A)

(IMP-B)

An extreme increase of impurities in amorphous canagliflozin already occurs if one of the load parameters is increased. In exposition to a high temperature and low relative humidity (80°C, 1% RH) or high humidity at the room temperature (RT, in the presence of water) an increase of chemical impurities on the percent order occurred and the chemical purity dropped from the original 100.00% to 94.98%, or 95.83% (HPLC), respectively. Under these conditions, the complex of canagliflozin with β-cyclodextrin is stable, the impurities do not increase and the complex manifests a stable purity of 100.00%. It is only at the combination of both the load parameters, a high temperature and high humidity (80°C, 75% RH) that the chemical purity of the complex decreases from the origmal 100.00% to 98.60% (HPLC). Under the conditions of a high temperature and low relative humidity (80°C, 1% RH) the complex of canagliflozin with β-cyclodextrin is more stable than the form of canagliflozin hemihydrate (described in the patent application WO2009035969). While the chemical purity of the complex of canagliflozin with β-cyclodextrin remained at 100.00% (HPLC), the chemical purity of the canagliflozin hemihydrate form (according to the patent application WO2009035969) decreased from the original 100.00% to 99.40% (HPLC).

Considering the polymorphic purity, a higher temperature and humidity also causes an undesired transformation of the amorphous form to the crystalline form of canagliflozin hemihydrate (according to the patent application WO2009035969).

Table 1: Comparison of the stability of amorphous canagliflozin and of the complex with β- cyclodextrin

Chemical purity (HPLC)

amorphous form β-CD complex

50°C, 15% RH, 72 h 100% 100%

50°C, 75% RH, 72 h 100% 100% 80°C, 1% RH, 72 h 94.98% 100%

80°C, 75% RH, 72 h 88.76% 98.60%

RT, 10 days in presence of P₂0₅ 100% 100%

RT, 10 days, in presence of water 95.83% 100%

Polymorphic stability (XRPD)

amorphous form β-CD complex

50°C, 15% RH, 72 h amorphous form β-CD complex

50°C, 75% RH, 72 h hemihydrate β-CD complex

80°C, 1% RH_S 72 h hemihydrate β-CD complex

80°C, 75% RH, 72 h hemihydrate β-CD complex

RT, 10 days in presence of Ρ₂0₅ amorphous form β-CD complex

RT, 10 days, in presence of water hemihydrate β-CD complex

It can be seen from the table above that amorphous canagliflozin is chemically and polymorphically stable if it is kept under an inert atmosphere (without access of humidity) and below 50°C. Compared to the amorphous form the complex of canagliflozin with β- cyclodextrin is much more resistant to humidity and higher temperatures. The contents of chemical impurities only start to increase at a combination of a high temperature and high humidity. In terms of polymorphic purity the above mentioned complex is highly stable and no phase transformation is observed.

Records of true dissolution (Fig. 11) and dissolution from powder (Fig. 12) were measured at physiological pH (phosphate buffer, pH 6.8). The records show that in both the cases the complex of canagliflozin with β-cyclodextrin exhibits a higher solubility than the amorphous and hemihydrate forms. A higher biological availability is also related to the higher solubility. The complexes of canagliflozin with β-cyclodextrin were characterized with the use of the X- ray powder diffraction. X-ray patterns corresponding to more or less crystalline samples were obtained. The patterns are shown in Figs. 4, 5 and 6. Figure 4 corresponds to the pattern of a β- cyclodextrin complex of canagliflozin having a mostly amorphous form with an intensive diffraction peak of 4.9° 2-theta. Figure 5 shows a β-cyclodextrin complex of canagliflozin where an excess of free β-cyclodextrin was detected (the β-CD pattern the bottom of in Fig. 5). Figure 6 in turn corresponds to a sample of a β-cyclodextrin complex of canagliflozin having a crystalline character with the following characteristic diffraction peaks: 4.7; 9.5; 13.6; 14.9; 16.5; 17.7; 19.1 and 21.4° ± 0.2° 2-theta.

A γ-cyclodextrin complex shows a distinctly crystalline character. The X-ray powder pattern of this complex is shown in Fig. 10. The characteristic peaks are: 7.6; 15.1; 16.9; 22.0 and 23.9 ± 0.2 2-theta. Diffraction peaks with a higher relative intensity than 15% are shown in Table 2.

The crystalline form of canagliflozin hemihydrate (according to the patent application WO2009035969) was not detected in any sample.

Table 2: Diffraction peaks of the γ-cyclodextrin complex of canagliflozin

Brief Description of Drawings

Fig. 1: ssNMR record of amorphous canagliflozin

Fig. 2: XRPD pattern of amorphous canagliflozin

Fig.3: DSC record of amorphous canagliflozin

Fig. 4: XRPD pattern of the β-cyclodextrin complex of canagliflozin of an amorphous

character Fig. 5: XRPD pattern of the β-cyclodextrin complex of canagliflozin with an excess of free β- cyclodextrin

Fig. 6: XRPD pattern of the β-cyclodextrin complex of canagliflozin of a crystalline character Fig. 7: ssNMR record of the β-cyclodextrin complex of canagliflozin of an amorphous

character

Fig. 8: ssNMR record of the β-cyclodextrin complex of canagliflozin of a crystalline character

Fig. 9: DSC record of the β-cyclodextrin complex of canagliflozin

Fig. 10: XRPD pattern of the crystalline complex of canagliflozin with γ-cyclodextrin

Fig. 11: Record of true dissolution - comparison of solubility of the β-cyclodextrin complex of canagliflozin (cana with beta CD), amorphous form of canagliflozin (cana amorph) and the crystalline hemihydrate of canagliflozin (cana hemi)

Fig. 12: Record of dissolution from powder - comparison of solubility of the β-cyclodextrin complex of canagliflozin (cana with beta CD), amorphous form of canagliflozin (cana amorph) and the crystalline hemihydrate of canagliflozin (cana hemi)

Examples

Amorphous canagliflozin was prepared according to the procedure published in the patent application WO05012326. The chemical purity of thus prepared crude amorphous canagliflozin was 99.48% (HPLC). The solid state NMR spectrum (Fig. 1), XRPD pattern (Fig. 2) as well as the DSC pattern (Fig. 3) confirm the amorphous form. 1H NMR (500 MHz, dmso-i¾): δ 2.26 (s, 3H₅ CHj); 3.12 - 3.28 (m₅ 4H, 4x CH-OH); 3.43 (m, 1H, CHj-OH); 3.70 (m, 1H, CH2-OH); 3.96 (d, J = 9.3 Hz, 1H, CH(O)-Ar); 4.12 (m, 2H, CHa-Ar); 4.44 (t_} J = 5.7 Hz, 1H, CH2-OH); 4.74 (d, J = 5.9 Hz, 1H, CH-OH); 4.94 (d, J = 4.7 Hz, 2H, 2x CH-OH); 6.80 (d, J = 3.4 Hz, 1H, Th); 7.13 (m, 2H, 2x CHA_T); 7.20 (m, 3H, 3x CHA_T); 7.28 (d, J = 3.7 Hz, 1H, Th); 7.59 (m, 2Η, 2x CH ). ¹³C NMR (125.8 MHz, dmso-itf): δ 18.8 (C¾); 33.5 (CH₂-Ar); 61.4 (CH₂-OH); 70.4 (CH-OH); 74.7 (CH-OH); 78.5 (CH-OH); 81.2 (CH-OH); 81.3 (CH(O)-Ar); 115.9 (J_CF = 21.8 Hz, CHA _f); 123.4 (Th); 126.3 (CR ); 126.4 (Th); 127.0 (JCF = 8.3 Hz, CHA_T_F); 129.1 (CHA_T); 129.7 (CU ); 130.5 (J_CF = 3.2 Hz, CA_T-f); 135.0 (C^); 137.4 (CA_T); 138.3 (CM); 140.2 (CA_T); 143.6 (C^); 161.4 (J_CF = 244.0 Hz, CA_T-F). Example 1

Preparation of a complex of canagliflozin with β-cyclodextrin in the 1:1 ratio

β-Cyclodextrin (300 mg, 0.225 mmol) was added to 4 ml of water and the resulting suspension was heated up to 100°C until dissolution. Crystalline canagliflozin hemihydrate (102 mg, 0.225 mmol) was gradually added to the resulting clear solution; then it got dissolved and subsequently began to be yielded in the form of the complex with β-cyclodextrin. After adding of all the canagliflozin the reaction mixture was agitated at 100°C for another about 5 minutes. Then it was left to slowly cool down to the room temperature and after that it was agitated in an ice bath for 30 minutes. The resulting crystalline substance was filtered, washed with 1 ml of icy water and dried in a vacuum drier at 25 °C overnight. 370 mg of a purely white substance was obtained with the chemical purity of 100.0% (HPLC).

Example 2

Preparation of a complex of canagliflozin with β-cyclodextrin

β-Cyclodextrin (9.26 g, 6.95 mmol) was added to 55 ml of water and the resulting suspension was heated up to 100°C until dissolution. Amorphous canagliflozin (3.00 g, 6.75 mmol) was gradually added to the resulting clear solution. After adding of all the amorphous canagliflozin the reaction mixture was agitated at 100°C for another about 15 minutes. Then it was left to slowly cool down to the room temperature and after that it was agitated in an ice bath for 60 minutes. The resulting crystalline substance was filtered, washed with 2 x 10 ml of icy water and dried in a vacuum drier at 25°C overnight. The amount of 11.4 mg of a purely white substance was obtained with the chemical purity of 99.9% (HPLC).

Example 3

Preparation of a complex of canagliflozin with γ-cyclodextrin

γ-Cyclodextrin (286 mg, 0.22 mmol) was added to 2 ml of water and the resulting solution was heated up to 100 °C. Amorphous canagliflozin (100 mg, 0.22 mmol) was gradually added. After adding of all the amorphous canagliflozin the reaction mixture was agitated at 100^oC for another about 5 minutes. Then it was left to slowly cool down to the room temperature and after that it was agitated in an ice bath for 30 minutes. The resulting crystalline substance was filtered, washed with 1 ml of icy water and dried in a vacuum drier at 25°C overnight. 350 mg of a purely white substance was obtained with the chemical purity of 99.85% (HPLC). Example 4

Preparation of a complex of canagliflozin with (2-hydroxyethyl)-p-cyclodextrin

(2-Hydroxyethyl)- -cyclodextrin (350 mg, 0.24 mmol) was added to 2 ml of water and the resulting suspension was heated up to 100°C until dissolution. Canagliflozin (100 mg, 0.22 mmol) was gradually added to the resulting clear solution; then it got dissolved and subsequently began to be yielded in the form of a complex with β-cyclodextrin. After adding of all the canagliflozin the reaction mixture was agitated at 100°C for another about 5 minutes. Then it was left to slowly cool down to the room temperature and after that it was agitated in an ice bath for 30 minutes and put in a fridge for 72 hours. The resulting crystalline substance was filtered, washed with 1 ml of icy water and dried in a vacuum drier at 25°C overnight 290 mg of a purely white substance was obtained with the chemical purity of 99.62% (HPLC).

Example 5

Preparation of a complex of canagliflozin with (2-hydroxypropyl)-p-cyclodextrin

(2-Hydroxypropyl)- -cyclodextrin (355 mg, 0.24 mmol) was added to 2 ml of water and the resulting suspension was heated up to 100°C until dissolution. Canagliflozin (100 g, 0.22 mmol) was gradually added to the resulting clear solution and then it got dissolved. After adding of all the canagliflozin the reaction mixture was agitated at 100°C for another about 5 minutes. Then it was left to slowly cool down to the room temperature and after that it was agitated in an ice bath for 30 minutes and put in a fridge for 72 hours. The resulting crystalline substance was filtered, washed with 1 ml of icy water and dried in a vacuum drier at 25°C overnight. 320 mg of a purely white substance was obtained with the chemical purity of 99.76% (HPLC).

Example 6

Preparation of a complex of canagliflozin with the sodium salt of sulf butyl ether-β- cyclodextrin

Sulfobutyl ether-P-cyclodextrin (353 mg, 0.24 mmol) was added to 2 ml of water and the resulting suspension was heated up until dissolution. Canagliflozin (100 mg, 0.22 mmol) was gradually added to the resulting clear solution at 100°C. After adding of all the canagliflozin the reaction mixture was agitated at 100°C for another about 5 minutes. Then it was left to slowly cool down to the room temperature and after that it was agitated in an ice bath for 30 minutes and put in a fridge for 72 hours. The resulting crystalline substance was filtered, washed with 1 ml of icy water and dried in a vacuum drier at 25°C overnight. 300 mg of a purely white substance was obtained with the chemical purity of 99.78% (HPLC).

Example 7

Preparation of a complex of canagliflozin with heptakis(2,3,6-tri-0-methyl)-p- cyclodextrin

Hep1akis(2,3_J6-tri-0-methyl)-p-cyclodextrin (347 mg₅ 0.24 mmol) was added to 2 ml of water and it got dissolved after about 5 min of agitation at 25°C. This solution was heated up to 100°C and at an elevated temperature the modified cyclodextrin started to be yielded. Canagliflozin (100 mg, 0.22 mmol) was added at 100°C and the suspension was agitated at this temperature for another 5 min. Then it was left to slowly cool down to the room temperature and after that it was agitated for 30 minutes in an ice bath and put in a fridge for 72 hours. The resulting crystalline substance was filtered, washed with 1 ml of icy water and dried in a vacuum drier at 25°C overnight. 275 mg of a purely white substance was obtained with the chemical purity of 99.92% (HPLC).

Example 8

Preparation of a complex of canagliflozin with heptakis(2,6-di-0-methyl)-p-cyclodextrin

Heptakis(2,6-di-0-memyI)-p-cyclodextrin (345 mg, 0.24 mmol) was added to 2 ml of water I and it got dissolved after approx. 5 min of agitation at 25°C. This solution was heated up to

100°C and at an elevated temperature the modified cyclodextrin started to be yielded.

Canagliflozin (100 mg, 0.22 mmol) was added at 100°C and the suspension was agitated at this temperature for another 5 min. Then it was left to slowly cool down to the room temperature and after that it was agitated in an ice bath for 30 minutes and put in a fridge for i 72 hours. The resulting crystalline substance was filtered, washed with 1 ml of icy water and dried in a vacuum drier at 25°C overnight. 260 mg of a purely white substance was obtained with the chemical purity of 99.90% (HPLC).

Example 9

) Example of purification of crude canagliflozin

β-Cyclodextrin (18.5 g, 13.9 mmol) was added to 110 ml of water and the resulting suspension was heated up to 100°C until dissolution. Crude amorphous canagliflozin (6.00 g, 13.5 mmol) with the chemical purity of 98.35% (HPLC) was gradually added to the resulting clear solution. After adding of all the canagliflozin the reaction mixture was agitated at 100°C for another about 15 minutes. Then it was left to slowly cool down to the room temperature and after that it was agitated in an ice bath for 60 minutes. The resulting crystalline substance - canagliflozin - was filtered, washed with 2 x 15 ml of icy water, 2 x 10 ml of acetone and dried in a vacuum drier at 25°C overnight 22.5 mg of a purely white substance was obtained with the chemical purity of 99.86% (HPLC).

Outline of analytic methods

Measurement parameters of XRPD: The diffraction patterns were measured using an X'PERT PRO MPD PANalytical diffractometer, used radiation CuKa (λ=1.542 A), excitation voltage: 45 kV, anode current: 40 mA, measured range: 2 - 40° 2Θ, increment: 0,01° 2Θ, the measurement was carried out on a flat powder sample that was applied on a Si plate. For the setting of the primary optical equipment programmable divergence slits with the irradiated area of the sample of 10 mm, 0.02 rad S oiler slits and a ¼° anti-diffusion slit were used. For the setting of the secondary optical equipment an X'Celerator detector with maximum opening of the detection slot, 0.02 rad Soller slits and a 5.0 mm anti-diffusion slit were used.

The nuclear magnetic resonance ( M ) spectra were measured using an Avance 500 device made by Bruker. 1H spectra were measured at the frequency of 500.13 MHz, ¹ C at the frequency of 125.8 MHz. The sample was measured in a deuterated solvent specified for the particular analysis, normally at 25 °C (unless specified otherwise for a particular analysis). The chemical shift δ is expressed as ppm, the interaction constants J are specified in Hz. The spectra were normally referenced to the residual solvent content.

Carbon spectra of solid-state nuclear magnetic resonance (ssNMR) were measured with the use of an Avance 400 WB Bruker device, using the CP/MAS method in a 4mm rotor at the speed of 13 kHz, normally at 25°C.

The records of differential scanning calorimetry (DSC) were measured using a Discovery DSC device made by TA Instruments. The sample charge in a standard Al pot (40 μΐ.) was between 9-10 mg and the heating rate was 5°C/min. The temperature program that was used consists of 5 min of stabilization at the temperature of 0°C and then of heating up to 200°C (for the mixture up to 220 °C) at the heating rate of 5°C/min (Amplitude = 0.8°C and Period = 60 s). As the carrier gas 5.0 N₂ was used at the flow of 50 ml/min.

Chemical purity was measured with the use of liquid chromatography (HPLC):

Device: Waters Acquity UPLC, PDA detection

Sample preparation: Dissolve 10.0 mg of the tested sample in 20.0 ml of 80% methanol Column: - dimension: 1 = 0.10 m, 0 = 2.1 mm

- stationary phase: Restek Pinnacle biphenyl, 1.9 μηι particles

- column temperature: 60°C.

Mob He phase: A 10 mM phosphate buffer at pH 2.5

B: methanol

Gradient elution:

Detection: spectrophotometer 220 nm

Injected quantity: 1 μΐ

Sample temperature: 20°C

Sample concentration: 0.5 mg ml

Solubility of canagliflozin was monitored by means of dissolution:

Dissolution from powder

Device: (Sirius T3 - UV detection) The experiment was carried out with three repetitions each time in 20ml vials with the use of a GI buffer (10 mM phosphate buffer and 3M KCl) with pH 6.8 at 25°C.

True dissolution

Device: Agilent dissolution device - UV detection

The experiment was carried out in three repetitions in 600 mL dissolution vessels with the use of a 50 mM phosphate buffer at pH 6.8 at 37°C.

Claims

1. A complex of canagliflozin with cyclodextrin.

2. The complex of canagliflozin with cyclodextrin according to claim 1, which has the character of an inclusion complex.

3. The complex according to claims 1 to 2, characterized in that cyclodextrin is selected from the group consisting of β-cyclodextrin, (2-hydroxyethyl)- -cyclodextrin, (2- hydroxypropyl)- -cyclodextrin, sodium salt of sulfobutyl ether-P-cyclodextrin, heptakis(2.3,6-tri-0-methyl)- -cyclodextrin and heptakis(2,6-di-0-methyl)-p- cyclodextrin, and γ-cyclodextrin.

4. The complex according to claims 1 to 3, characterized in that the molar ratio of cyclodextrin to canagliflozin is in the range of from 0.5 : 1 to 2 : 1.

5. The complex according to claim 4, characterized in that the molar ratio of cyclodextrin to canagliflozin is 1 : 1.

6. A method for preparing the complex of canagliflozin and cyklodextrin as defined in claims 1 to 5, comprising the following steps:

a) dissolving or dispersing the cyclodextrin in a solvent;

b) adding canagliflozin;

c) removing the solvents from the mixture from step b), preferably by lyophiiization, spray drying, or filtration.

7. The preparation method according to claim 6, characterized in that the cyclodextrin is selected from the group consisting of β-cyclodextrin, (2-hydroxyethyl)-P-cyclodextrin, (2-hydroxypropyl)-P-cyclodextrin, sodium salt of sulfobutyl ether- -cyclodextrin, heptakis(2,3 ,6-tri-0-methyi)-p-cyclodextrin and heptakis(2,6-di-0-methyl)- - cyclodextrin, and γ-cyclodextrin.

8. The preparation method according to claim 7, characterized in that the cyclodextrin is selected from the group consisting of β-cyclodextrin, (2-hydroxy)propyl-p-cyclodextrin, and γ-cyclodextrin.

9. A pharmaceutical composition, characterized in that it contains the complex of canagliflozin with cyclodextrin according to any one of claims 1 to 5.

10. Use of the complex of canagliflozin with cyclodextrin according to claims 1 to 5 for the preparation of canagliflozin of a high chemical purity of at least 99.85% HPLC.